Publications by authors named "Sabine Defoort-Dhellemmes"

45 Publications

Retinal Phenotype of Patients With Isolated Retinal Degeneration Due to CLN3 Pathogenic Variants in a French Retinitis Pigmentosa Cohort.

JAMA Ophthalmol 2021 Mar;139(3):278-291

Sorbonne Université, INSERM, Centre national de la recherche scientifique, Institut de la Vision, Paris, France.

Importance: Biallelic variants in CLN3 lead to a spectrum of diseases, ranging from severe neurodegeneration with retinal involvement (juvenile neuronal ceroid lipofuscinosis) to retina-restricted conditions.

Objective: To provide a detailed description of the retinal phenotype of patients with isolated retinal degeneration harboring biallelic CLN3 pathogenic variants and to attempt a phenotype-genotype correlation associated with this gene defect.

Design, Setting, And Participants: This retrospective cohort study included patients carrying biallelic CLN3 variants extracted from a cohort of patients with inherited retinal disorders (IRDs) investigated at the National Reference Center for Rare Ocular Diseases of the Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts from December 2007 to August 2020. Data were analyzed from October 2019 to August 2020.

Main Outcome And Measures: Functional (best-corrected visual acuity, visual field, color vision, and full-field electroretinogram), morphological (multimodal retinal imaging), and clinical data from patients were collected and analyzed. Gene defect was identified by either next-generation sequencing or whole-exome sequencing and confirmed by Sanger sequencing, quantitative polymerase chain reaction, and cosegregation analysis.

Results: Of 1533 included patients, 843 (55.0%) were women and 690 (45.0%) were men. A total of 15 cases from 11 unrelated families harboring biallelic CLN3 variants were identified. All patients presented with nonsyndromic IRD. Two distinct patterns of retinal disease could be identified: a mild rod-cone degeneration of middle-age onset (n = 6; legal blindness threshold reached by 70s) and a severe retinal degeneration with early macular atrophic changes (n = 9; legal blindness threshold reached by 40s). Eleven distinct pathogenic variants were detected, of which 4 were novel. All but 1, p.(Arg405Trp), CLN3 point variants and their genotypic associations were clearly distinct between juvenile neuronal ceroid lipofuscinosis and retina-restricted disease. Mild and severe forms of retina-restricted CLN3-linked IRDs also had different genetic background.

Conclusions And Relevance: These findings suggest CLN3 should be included in next-generation sequencing panels when investigating patients with nonsyndromic rod-cone dystrophy. These results document phenotype-genotype correlations associated with specific variants in CLN3. However, caution seems warranted regarding the potential neurological outcome if a pathogenic variant in CLN3 is detected in a case of presumed isolated IRD for the onset of neurological symptoms could be delayed.
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http://dx.doi.org/10.1001/jamaophthalmol.2020.6089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844693PMC
March 2021

Variable Presentation of Leber Hereditary Optic Neuropathy in Children of a Family Harboring a Rare m.13051G>A mtDNA Mutation.

J Neuroophthalmol 2020 12;40(4):569-571

Exploration de la Vision et Neuro-Ophtalmologie (VMS, CM, PD, SD-D), CHU de Lille, Lille, France; Université de Lille (VMS), Faculté de Médecine, Lille Cedex, France; Neurologie pédiatrique (J-MC), CHU de Lille, Lille, France; and Université de Lille (C-MD), Inserm UMRS 1172, CHU Lille, Biochemistry and Molecular Biology Department UF Génopathies, Lille, France.

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http://dx.doi.org/10.1097/WNO.0000000000001083DOI Listing
December 2020

LIPE-related lipodystrophic syndrome: clinical features and disease modeling using adipose stem cells.

Eur J Endocrinol 2021 Jan;184(1):155-168

Sorbonne Université, Inserm UMRS_938, Centre de Recherche Saint Antoine, Paris, France.

Objective: The term Multiple Symmetric Lipomatosis (MSL) describes a heterogeneous group of rare monogenic disorders and multifactorial conditions, characterized by upper-body adipose masses. Biallelic variants in LIPE encoding hormone-sensitive lipase (HSL), a key lipolytic enzyme, were implicated in three families worldwide. We aimed to further delineate LIPE-related clinical features and pathophysiological determinants.

Methods: A gene panel was used to identify pathogenic variants. The disease features were reviewed at the French lipodystrophy reference center. The immunohistological, ultrastructural, and protein expression characteristics of lipomatous tissue were determined in surgical samples from one patient. The functional impact of variants was investigated by developing a model of adipose stem cells (ASCs) isolated from lipomatous tissue.

Results: We identified new biallelic LIPE null variants in three unrelated patients referred for MSL and/or partial lipodystrophy. The hallmarks of the disease, appearing in adulthood, included lower-limb lipoatrophy, upper-body and abdominal pseudo-lipomatous masses, diabetes and/or insulin resistance, hypertriglyceridemia, liver steatosis, high blood pressure, and neuromuscular manifestations. Ophthalmological investigations revealed numerous auto-fluorescent drusen-like retinal deposits in all patients. Lipomatous tissue and patient ASCs showed loss of HSL and decreased expression of adipogenic and mature adipocyte markers. LIPE-mutated ASCs displayed impaired adipocyte differentiation, decreased insulin response, defective lipolysis, and mitochondrial dysfunction.

Conslusions: Biallelic LIPE null variants result in a multisystemic disease requiring multidisciplinary care. Loss of HSL expression impairs adipocyte differentiation, consistent with the lipodystrophy/MSL phenotype and associated metabolic complications. Detailed ophthalmological examination could reveal retinal damage, further pointing to the nervous tissue as an important disease target.
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http://dx.doi.org/10.1530/EJE-20-1013DOI Listing
January 2021

Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy.

Neurol Genet 2020 Jun 20;6(3):e428. Epub 2020 May 20.

MitoLab Team (M.C., A.C., C.B., D.G., V.D.-D., S.L., V.P., P.R., D.B., P.A.-B., G.L.), UMR CNRS 6015-INSERM U1083, Institut MitoVasc, Angers University and Hospital; Genetics and immuno-cell therapy Team (M.C.), Mohammed First University, Oujda, Morocco; Departments of Biochemistry and Genetics (C.B., D.G., V.D.-D., E.C., V.P., P.R., D.B., P.A.-B.), University Hospital Angers; Department of Ophthalmology (A.M.), Centre Hospitalier Universitaire Saint-Pierre, Brussels, Belgium; Neuroophthalmology Department (C.V.), Rothschild Ophthalmologic Foundation, Paris; Exploration of Visual Function and Neuro-Ophthalmology Department (V.S., S.D.-D., I.D.B.), Lille University Hospital, Rue Emilie Laine, Lille Cedex; CHU Bordeaux (C.G.), Service de Génétique Médicale, Centre de Référence « Neurogénétique » and Université de Bordeaux, INSERM U 1211, Laboratoire Maladies Rares, Génétique et Métabolisme (MRGM) Bordeaux; School of Optometry and Vision Sciences (M.V.), Cardiff University and Cardiff Eye Unit, University Hospital of Wales; NIHR Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology (N.J., P.Y.-W.-M.), London; Department of Clinical Neurosciences (P.Y.-W.-M.), Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit, University of Cambridge; Cambridge Eye Unit (P.Y.-W.-M.), Addenbrooke's Hospital, Cambridge University Hospitals, UK; IRCCS Istituto Delle Scienze Neurologiche di Bologna (F.T., L.C., C.L.M., V.C.), Bellaria Hospital; Unit of Neurology (C.L.M., V.C.), Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Italy; Centre de Compétence Maladies Rares (X.Z.), Clinique Pluridisciplinaire Jules Verne, Nantes; and National Centre in Rare Diseases (I.M.), Genetics of Sensory Diseases, University Hospital, Montpellier, France.

Objective: To improve the genetic diagnosis of dominant optic atrophy (DOA), the most frequently inherited optic nerve disease, and infer genotype-phenotype correlations.

Methods: Exonic sequences of 22 genes were screened by new-generation sequencing in patients with DOA who were investigated for ophthalmology, neurology, and brain MRI.

Results: We identified 7 and 8 new heterozygous pathogenic variants in and . Both genes encode for mitochondrial matricial AAA (m-AAA) proteases, initially involved in recessive hereditary spastic paraplegia type 7 (HSP7) and dominant spinocerebellar ataxia 28 (SCA28), respectively. Notably, variants in that result in DOA are located in different domains to those reported in SCA28, which likely explains the lack of clinical overlap between these 2 phenotypic manifestations. In comparison, the variants identified in DOA are interspersed among those responsible for HSP7 in which optic neuropathy has previously been reported.

Conclusions: Our results position and as candidate genes to be screened in DOA and indicate that regulation of mitochondrial protein homeostasis and maturation by m-AAA proteases are crucial for the maintenance of optic nerve physiology.
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http://dx.doi.org/10.1212/NXG.0000000000000428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251510PMC
June 2020

Description of Two Siblings with Apparently Severe CEP290 Mutations and Unusually Mild Retinal Disease Unrelated to Basal Exon Skipping or Nonsense-Associated Altered Splicing.

Adv Exp Med Biol 2019 ;1185:189-195

Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetics Diseases, Imagine and Paris Descartes University, Paris, France.

CEP290 mutations cause a spectrum of ciliopathies, including Leber congenital amaurosis. Milder retinal diseases have been ascribed to exclusion of CEP290 mutant exons through basal exon skipping (BES) and/or nonsense-associated altered splicing (NAS). Here, we report two siblings with some preserved vision despite biallelism for presumably severe CEP290 mutations: a maternal splice site change in intron 18 (c.1824 + 3A > G) and a paternal c.6869dup (p.Asn2290Lysfs∗6) in exon 50 that introduces a premature termination codon (PTC) within the same exon. Analyzing mRNAs from fibroblasts of the two siblings, we detected no BES or NAS which could have enabled the production of PTC-free CEP290 isoforms from the paternal allele. In contrast, we reveal partial alteration of exon 18 donor splice site, allowing the transcription of some correctly spliced CEP290 mRNAs from the maternal allele which likely account for the mild retinal disease. This observation adds further variability to the mechanisms underlying CEP290 pleiotropy.
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http://dx.doi.org/10.1007/978-3-030-27378-1_31DOI Listing
February 2020

Pigmented paravenous chorioretinal atrophy revealing a chronic granulomatous disease.

Ophthalmic Genet 2019 10 19;40(5):470-473. Epub 2019 Oct 19.

Exploration de la Vision et Neuro-Ophtalmologie, CHU Lille, Lille, France.

: Pigmented Paravenous Chorioretinal Atrophy (PPCRA) is a rare and predominantly sporadic form of chorioretinal atrophy. Ocular and systemic inflammation has been considered a possible etiology of PPCRA. In this report, we describe an unusual case of PPCRA in a child who was recently diagnosed with chronic granulomatous disease.: A 4-year-old boy was referred for ophthalmic assessment after a seizure. Fundus examination revealed atrophic chorioretinal lesions typical of PPCRA. We had also referred this patient to a gastroenterologist for chronic abdominal pain and diarrhea. The patient was first diagnosed as a case of Crohn's disease, but in the setting of mesenteric lymphadenopathy, a workup for immune dysfunction was performed. Nitro-blue tetrazolium test (NBT) was negative, suggesting a chronic granulomatous disease, which was finally confirmed by genetic testing.: The presentation of PPCRA has been sporadic in the majority of cases. Inflammatory and hereditary origins have been anecdotally cited. Our young patient showed concurrent presentation of inflammatory and hereditary origin of PPCRA. We suggest that a careful investigation of systemic inflammation should be done in children with suggestive extraocular symptoms in the setting of PPCRA.
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http://dx.doi.org/10.1080/13816810.2019.1681009DOI Listing
October 2019

Severe retinitis pigmentosa with posterior staphyloma in a family with c.886C>A p.(Lys296Glu) mutation.

Ophthalmic Genet 2019 08 22;40(4):365-368. Epub 2019 Aug 22.

Biochemistry and Molecular Biology Department - UF Génopathies, Univ Lille , Lille , France.

: Posterior pole staphylomata (PSS) is an outward bulging of ocular wall, rarely reported in association with inherited retinal degenerations. : We report a large French family of Jewish ancestry with a peculiar form of dominant retinitis pigmentosa (RP) and posterior pole staphyloma (PPS). Eight members were clinically and genetically examined. : All affected members complained of night blindness from early childhood and their ERGs were extinguished in the first decade of life. Seven out of eight presented PPS on fundus examination and SD-OCT. The youngest patient did not present PPS at 11 months of age, but the signs of posterior pole bowing became evident at age 8 years. There was no association between the presence of PPS and refraction. Patients with PPS were either hyperopic or myopic, but all have a high with-the-rule astigmatism. A myopic shift was observed for all of them at follow-up. In this family, the disease segregated with the c.886A>G mutation in gene. : A PPS development was observed in initially non-myopic patients of a family with unusually severe dominant RP. The PPS concerned only the area with relatively preserved outer retinal layers (outer nuclear layer and ellipsoid zone). How the outer retina could guide choroid and scleral remodelling remains unclear.
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http://dx.doi.org/10.1080/13816810.2019.1655771DOI Listing
August 2019

AON-Mediated Exon Skipping to Bypass Protein Truncation in Retinal Dystrophies Due to the Recurrent c.4723A > T Mutation. Fact or Fiction?

Genes (Basel) 2019 05 14;10(5). Epub 2019 May 14.

Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetics Diseases, Imagine and Paris Descartes University, 75015 Paris, France.

Mutations in encoding a centrosomal protein important to cilia formation cause a spectrum of diseases, from isolated retinal dystrophies to multivisceral and sometimes embryo-lethal ciliopathies. In recent years, endogenous and/or selective non-canonical exon skipping of mutant exons have been documented in attenuated retinal disease cases. This observation led us to consider targeted exon skipping to bypass protein truncation resulting from a recurrent mutation in exon 36 (c.4723A > T, p.Lys1575*) causing isolated retinal ciliopathy. Here, we report two unrelated individuals (P1 and P2), carrying the mutation in homozygosity but affected with early-onset severe retinal dystrophy and congenital blindness, respectively. Studying skin-derived fibroblasts, we observed basal skipping and nonsense associated-altered splicing of exon 36, producing low (P1) and very low (P2) levels of CEP290 products. Consistent with a more severe disease, fibroblasts from P2 exhibited reduced ciliation compared to P1 cells displaying normally abundant cilia; both lines presented however significantly elongated cilia, suggesting altered axonemal trafficking. Antisense oligonucleotides (AONs)-mediated skipping of exon 36 increased the abundance of the premature termination codon (PTC)-free mRNA and protein, reduced axonemal length and improved cilia formation in P2 but not in P1 expressing higher levels of skipped mRNA, questioning AON-mediated exon skipping to treat patients carrying the recurrent c.4723A > T mutation.
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http://dx.doi.org/10.3390/genes10050368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562928PMC
May 2019

Clinical and molecular findings of FRMD7 related congenital nystagmus as adifferential diagnosis of ocular albinism.

Ophthalmic Genet 2019 04 3;40(2):161-164. Epub 2019 Apr 3.

a Service de Génétique Médicale , CHU de Bordeaux , Bordeaux , France.

Background: Congenital nystagmus is one of the most common neuro-ophthalmological disorders. X chromosome-linked forms are associated with pathogenic variants of the GPR143 and FRMD7 genes.

Materials And Methods: Patients' DNA was analyzed using a next-generation sequencing (NGS) panel of genes involved in albinism and related pathologies (TYR, OCA2, TYRP1, SLC45A2, SLC24A5, C10ORF11, GPR143, SLC38A8, HPS 1 to 10, LYST, MITF, FRMD7) Results: We report a 4 generation family with 5 affected members initially referred for molecular diagnosis of ocular albinism. A missense variant of FRMD7 was found in 3 affected cases and one female carrier. We show that the disease in the affected girl is due to skewed inactivation of the X chromosome.

Conclusions: By compiling all the published cases we discuss the variable penetrance among females due to different types of mutation and to X-inactivation.
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http://dx.doi.org/10.1080/13816810.2019.1592201DOI Listing
April 2019

Where are the missing gene defects in inherited retinal disorders? Intronic and synonymous variants contribute at least to 4% of CACNA1F-mediated inherited retinal disorders.

Hum Mutat 2019 06 28;40(6):765-787. Epub 2019 Mar 28.

INSERM, CNRS, Institut de la Vision, Sorbonne Université, Paris, France.

Inherited retinal disorders (IRD) represent clinically and genetically heterogeneous diseases. To date, pathogenic variants have been identified in ~260 genes. Albeit that many genes are implicated in IRD, for 30-50% of the cases, the gene defect is unknown. These cases may be explained by novel gene defects, by overlooked structural variants, by variants in intronic, promoter or more distant regulatory regions, and represent synonymous variants of known genes contributing to the dysfunction of the respective proteins. Patients with one subgroup of IRD, namely incomplete congenital stationary night blindness (icCSNB), show a very specific phenotype. The major cause of this condition is the presence of a hemizygous pathogenic variant in CACNA1F. A comprehensive study applying direct Sanger sequencing of the gene-coding regions, exome and genome sequencing applied to a large cohort of patients with a clinical diagnosis of icCSNB revealed indeed that seven of the 189 CACNA1F-related cases have intronic and synonymous disease-causing variants leading to missplicing as validated by minigene approaches. These findings highlight that gene-locus sequencing may be a very efficient method in detecting disease-causing variants in clinically well-characterized patients with a diagnosis of IRD, like icCSNB.
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http://dx.doi.org/10.1002/humu.23735DOI Listing
June 2019

Unique noncoding variants upstream of PRDM13 are associated with a spectrum of developmental retinal dystrophies including progressive bifocal chorioretinal atrophy.

Hum Mutat 2019 05 14;40(5):578-587. Epub 2019 Feb 14.

UCL Institute of Ophthalmology, University College London, London, United Kingdom.

The autosomal dominant progressive bifocal chorioretinal atrophy (PBCRA) disease locus has been mapped to chromosome 6q14-16.2 that overlaps the North Carolina macular dystrophy (NCMD) locus MCDR1. NCMD is a nonprogressive developmental macular dystrophy, in which variants upstream of PRDM13 have been implicated. Whole genome sequencing was performed to interrogate structural variants (SVs) and single nucleotide variants (SNVs) in eight individuals, six affected individuals from two families with PBCRA, and two individuals from an additional family with a related developmental macular dystrophy. A SNV (chr6:100,046,804T>C), located 7.8 kb upstream of the PRDM13 gene, was shared by all PBCRA-affected individuals in the disease locus. Haplotype analysis suggested that the variant arose independently in the two families. The two affected individuals from Family 3 were screened for rare variants in the PBCRA and NCMD loci. This revealed a de novo variant in the proband, 21 bp from the first SNV (chr6:100,046,783A>C). This study expands the noncoding variant spectrum upstream of PRDM13 and suggests altered spatio-temporal expression of PRDM13 as a candidate disease mechanism in the phenotypically distinct but related conditions, NCMD and PBCRA.
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http://dx.doi.org/10.1002/humu.23715DOI Listing
May 2019

Extreme myopia in a family with a missense PAX6 mutation: extended phenotype.

Ophthalmic Genet 2019 02 28;40(1):64-65. Epub 2018 Dec 28.

a Exploration of Vision and Neuro-ophthalmology Department , Lille University Hospital , Lille , France.

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http://dx.doi.org/10.1080/13816810.2018.1558260DOI Listing
February 2019

Mild form of oculocutaneous albinism type 1: phenotypic analysis of compound heterozygous patients with the R402Q variant of the gene.

Br J Ophthalmol 2019 09 24;103(9):1239-1247. Epub 2018 Nov 24.

Service de génétique médicale, CHU de Bordeaux, Bordeaux, France.

Aim: Oculocutaneous albinism type 1 (OCA1) is due to mutations. c.1205G>A/p.Arg402Gln (R402Q) is a thermosensitive variant of the gene that has been reported to be responsible for mild forms of OCA1. The aim of our study was to define the phenotype associated with this variant.

Methods: In our retrospective series, among 268 patients diagnosed with OCA1, 122 (45.5%) harboured one pathogenic variant of , and the R402Q variant ensured to be in trans by segregation analysis in 69 patients (25.7%), constituting the 'R402Q-OCA1' group. 146 patients harboured two pathogenic variants of the gene other than R402Q. Clinical records were available for 119 of them, constituting the 'Classical-OCA1' group.

Results: Most R402Q-OCA1 patients presented with white or yellow-white hair at birth (71.43%), blond hair later (46.97%), a light phototype but with residual pigmentation (69.64%), and blue eyes (76.56%). Their pigmentation was significantly higher than in the classical-OCA1 group. All patients from the R402Q-OCA1 group presented with ocular features of albinism. However the prevalence of photophobia (78.13%) and iris transillumination (83.87%) and the severity scores of iris transillumination, retinal hypopigmentation and foveal hypoplasia were lower in the R402Q-OCA1 group. Visual acuity was higher in the R402Q-OCA1 group (0.38±0.21 logarithm of the minimum angle of resolution vs 0.76±0.24). Investigations concerning a possible additive effect of the c.575C>A/p.Ser192 (S192Y) variant of in cis with R402Q, suggested by others, showed no significant impact on the phenotype.

Conclusion: The R402Q variant leads to variable but generally mild forms of albinism whose less typical presentation may lead to underdiagnosis.
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http://dx.doi.org/10.1136/bjophthalmol-2018-312729DOI Listing
September 2019

Dietary, environmental, and genetic risk factors of Extensive Macular Atrophy with Pseudodrusen, a severe bilateral macular atrophy of middle-aged patients.

Sci Rep 2018 05 1;8(1):6840. Epub 2018 May 1.

Centre de Référence Maladies Sensorielles Génétiques, Hôpital Gui de Chauliac, University of Montpellier, Institute for Neurosciences of Montpellier INSERM U1051, Montpellier, France.

EMAP (Extensive Macular Atrophy with Pseudodrusen) is a maculopathy we recently described that shares pseudodrusen and geographic atrophy with Age-related Macular Disease (AMD). EMAP differs from AMD by an earlier age of onset (50-55 years) and a characteristic natural history comprising a night blindness followed by a severe visual loss. In a prospective case-control study, ten referral centers included 115 EMAP (70 women, 45 men) patients and 345 matched controls to appraise dietary, environmental, and genetic risk factors. The incidence of EMAP (mean 2.95/1.10) was lower in Provence-Côte d'Azur with a Mediterranean diet (1.9/1.10), and higher in regions with intensive farming or industrialized activities (5 to 20/1.10). EMAP patients reported toxic exposure during professional activities (OR 2.29). The frequencies of common AMD complement factor risk alleles were comparable in EMAP. By contrast, only one EMAP patient had a rare AMD variant. This study suggests that EMAP could be a neurodegenerative disorder caused by lifelong toxic exposure and that it is associated with a chronic inflammation and abnormal complement pathway regulation. This leads to diffuse subretinal deposits with rod dysfunction and cone apoptosis around the age of 50 with characteristic extensive macular atrophy and paving stones in the far peripheral retina.
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http://dx.doi.org/10.1038/s41598-018-25003-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931512PMC
May 2018

Retinal findings in a patient of French ancestry with CABP4-related retinal disease.

Doc Ophthalmol 2018 04 10;136(2):135-143. Epub 2018 Mar 10.

Exploration of Vision and Neuro-Ophthalmology Department, Lille University Hospital, Rue Emilie Laine, 59037, Lille Cedex, France.

Introduction: CABP4-related retinal dysfunction is a cone-rod synaptic transmission disorder with electronegative electroretinogram (ERG) waveform. It is a rare retinal dysfunction that can be classified into the incomplete form of congenital stationary night blindness. Absent foveal reflex and overall foveal thinning were previously reported, but in most cases the fundus appearance was described as nearly normal. We report here peculiar macular changes in a patient of French ancestry harbouring CABP4 mutations.

Methods: Complete ocular examination and full-field ERG were performed at the initial presentation and follow-up. Multimodal fundus imagining, including spectral-domain optical coherence tomography, colour, infrared reflectance and short-wavelength autofluorescence photographs, was performed during follow-up visits.

Results: A 7-month-old infant was addressed to our department for visual unresponsiveness and nystagmus. ERG had an electronegative waveform, even for light-adapted stimuli, thus supporting the diagnosis of photoreceptor-bipolar cell transmission disorder. Genetic investigations discovered a compound heterozygous mutation in CABP4: c.646C > T, p.Arg216*/c.673C > T, p.Arg225*. Multimodal fundus imaging, performed at follow-up visits, showed fine radial folds at the vitreomacular interface and dark foveal dots in both eyes. Optic coherence tomography revealed a focal foveal ellipsoid zone gap.

Discussion: Initial presentation was misleading with Leber congenital amaurosis. The electronegative ERG waveform reoriented the genetic investigations and thus establishing a correct diagnosis. To the best of our knowledge, the peculiar fundus changes observed in our patient were never reported before. We hypothesized that a foveal ellipsoid zone interruption discovered in our patient could reflect mostly a cone dysfunction. It was unclear whether the fine radial folds in both maculae were linked with high hyperopia or were an intrinsic feature of the retinal disease.

Conclusion: CABP4-related retinal disease is a cone-rod system disorder with possible foveal abnormalities.
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http://dx.doi.org/10.1007/s10633-018-9629-yDOI Listing
April 2018

A novel duplication of PRMD13 causes North Carolina macular dystrophy: overexpression of PRDM13 orthologue in drosophila eye reproduces the human phenotype.

Hum Mol Genet 2017 11;26(22):4367-4374

Institute for Neurosciences of Montpellier INSERM U1051, University of Montpellier, Montpellier, France.

In this study, we report a novel duplication causing North Carolina macular dystrophy (NCMD) identified applying whole genome sequencing performed on eight affected members of two presumed unrelated families mapping to the MCDR1 locus. In our families, the NCMD phenotype was associated with a 98.4 kb tandem duplication encompassing the entire CCNC and PRDM13 genes and a common DNase 1 hypersensitivity site. To study the impact of PRDM13 or CCNC dysregulation, we used the Drosophila eye development as a model. Knock-down and overexpression of CycC and CG13296, Drosophila orthologues of CCNC and PRDM13, respectively, were induced separately during eye development. In flies, eye development was not affected, while knocking down either CycC or CG13296 mutant models. Overexpression of CycC also had no effect. Strikingly, overexpression of CG13296 in Drosophila leads to a severe loss of the imaginal eye-antennal disc. This study demonstrated for the first time in an animal model that overexpression of PRDM13 alone causes a severe abnormal retinal development. It is noteworthy that mutations associated with this autosomal dominant foveal developmental disorder are frequently duplications always including an entire copy of PRDM13, or variants in one DNase 1 hypersensitivity site at this locus.
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http://dx.doi.org/10.1093/hmg/ddx322DOI Listing
November 2017

A new autosomal dominant eye and lung syndrome linked to mutations in TIMP3 gene.

Sci Rep 2016 09 7;6:32544. Epub 2016 Sep 7.

Institute for Neurosciences of Montpellier U1051, University of Montpellier-University Hospital, Genetics of Sensory Diseases, Montpellier, France.

To revisit the autosomal dominant Sorsby fundus dystrophy (SFD) as a syndromic condition including late-onset pulmonary disease. We report clinical and imaging data of ten affected individuals from 2 unrelated families with SFD and carrying heterozygous TIMP3 mutations (c.572A > G, p.Y191C, exon 5, in family 1 and c.113C > G, p.S38C, exon 1, in family 2). In family 1, all SFD patients older than 50 (two generations) had also a severe emphysema, despite no history of smoking or asthma. In the preceding generation, the mother died of pulmonary emphysema and she was blind after the age of 50. Her two great-grandsons (<20 years), had abnormal Bruch Membrane thickness, a sign of eye disease. In family 2, eye and lung diseases were also associated in two generations, both occurred later, and lung disease was moderate (bronchiectasis). This is the first report of a syndromic SFD in line with the mouse model uncovering the role of TIMP3 in human lung morphogenesis and functions. The TIMP3 gene should be screened in familial pulmonary diseases with bronchiectasis, associated with a medical history of visual loss. In addition, SFD patients should be advised to avoid tobacco consumption, to practice sports, and to undergo regular pulmonary examinations.
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http://dx.doi.org/10.1038/srep32544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013278PMC
September 2016

Long-term follow-up of two patients with oligocone trichromacy.

Doc Ophthalmol 2015 Oct 3;131(2):149-58. Epub 2015 Jul 3.

Exploration of Visual Function and Neuro-Ophthalmology Department, Lille University Hospital, Rue Emilie Laine, 59037, Lille Cedex, France.

Introduction: Oligocone trichromacy (OT) is an uncommon cone dysfunction disorder, the mechanism of which remains poorly understood. OT has been thought to be non-progressive, but its long-term visual outcome has been seldom reported in the literature. Our aim was to present two OT patients followed at our institution over 18 years.

Materials And Methods: Complete ocular examination, color vision, visual fields, and full-field electroretinography (ERG) were performed at initial presentation and follow-up. Spectral-domain optical coherence tomography (OCT) was performed during follow-up when available at our institution.

Results: Initial ocular examination showed satisfactory visual acuities with normal fundus examination and near-to-normal color vision. However, computerized perimetry demonstrated a ring-shaped scotoma around fixation, and ERG showed a profound cone dysfunction. The discrepancy between preserved color vision and profound cone dysfunction leads to the diagnosis of OT. Subsequent follow-ups over 18 years showed subtle degradation of visual acuities along with progression of the myopia in both patients and slight worsening of color vision in one patient. Initial OCT revealed a focal interruption of the ellipsoid line along with decreased thickness of the perifoveal macula. Subsequent OCT imaging performed 2 years later did not show any macular changes.

Conclusion: Although OT is known to be a non-progressive cone dysfunction, our results suggest that subtle degradation of the visual function might happen over time.
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http://dx.doi.org/10.1007/s10633-015-9508-8DOI Listing
October 2015

Predominantly Cone-System Dysfunction as Rare Form of Retinal Degeneration in Patients With Molecularly Confirmed Bardet-Biedl Syndrome.

Am J Ophthalmol 2015 Aug 15;160(2):364-372.e1. Epub 2015 May 15.

Service de Génétique Médicale, Institut de Génétique Médicale d'Alsace, Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO), Strasbourg, France; Laboratoire de Génétique Médicale, Institut de Génétique Médicale d'Alsace, INSERM U1112, Faculté de Médecine, Université de Strasbourg, Strasbourg, France. Electronic address:

Purpose: To describe a series of patients with Bardet-Biedl syndrome (BBS) and predominantly retinal cone dysfunction, a previously only rarely reported association.

Design: Retrospective observational case series.

Methods: Seven patients with clinically proven Bardet-Biedl syndrome had undergone detailed ocular phenotyping, which included fundus examination, Goldmann visual fields, fundus autofluorescence imaging (FAF), optical coherence tomography (OCT), and electroretinography (ERG). Mutational screening in the BBS genes was performed either by direct Sanger sequencing or targeted next-generation sequencing.

Results: All 7 patients had proven BBS mutations; 1 had a cone dystrophy phenotype on ERG and 6 had a cone-rod pattern of dysfunction. Macular atrophy was present in all patients, usually with central hypofluorescence surrounded by a continuous hyperfluorescent ring on fundus autofluorescence imaging. OCT confirmed loss of outer retinal structure within the atrophic areas. No clear genotype-phenotype relationship was evident.

Conclusions: Patients with Bardet-Biedl syndrome usually develop early-onset retinitis pigmentosa. In contrast, the patients described herein, with molecularly confirmed Bardet-Biedl syndrome, developed early cone dysfunction, including the first reported case of a cone dystrophy phenotype associated with the disorder. The findings significantly expand the phenotype associated with Bardet-Biedl syndrome.
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http://dx.doi.org/10.1016/j.ajo.2015.05.007DOI Listing
August 2015

A comparative optical coherence tomography study in neuromyelitis optica spectrum disorder and multiple sclerosis.

Mult Scler 2015 Dec 31;21(14):1781-93. Epub 2015 Mar 31.

Department of Neurology, University of Lille, France.

Objectives: The aim of this study was to find, using spectral domain-optical coherence tomography (SD-OCT), retinal imaging biomarkers differentiating neuromyelitis optica spectrum disorder (NMOSD), multiple sclerosis (MS) and healthy controls (HCs).

Materials And Methods: The population was composed of patients with NMOSD (n=23) or MS (n=110) and of HCs (n=75). Evaluation criteria were retinal thickness/volume, visual acuity, low contrast vision acuity and Expanded Disability Status Scale score.

Results: Considering all eyes and after statistical adjustments including the number of optic neuritis (ON) episodes, we found that NMOSD patients did not have significantly more retinal atrophy than MS patients; whereas MS non-optic neuritis (NON) eyes had thinner temporal (p=0.032) and temporo-superior peripapillary retinal nerve fibre layer (pRNFL; p=0.011) thicknesses than NMOSD NON eyes; in addition, NMOSD NON eyes presented significant naso-inferior pRNFL (p=0.024), temporal pRNFL (p=0.039), macular ganglion cell complex (p=0.004) and ganglion cell layer (p=0.002) atrophy vs HC eyes. We identified significant correlations between visual and clinical disability and retinal thicknesses in both diseases.

Conclusion: OCT may help to differentiate NMOSD and MS by focusing on the NON eyes (temporal pRNFL atrophy more severe in MS). Moreover, we discuss the possibility of a retinal degenerative process independent of ON in NMOSD.
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http://dx.doi.org/10.1177/1352458515578888DOI Listing
December 2015

High prevalence of PRPH2 in autosomal dominant retinitis pigmentosa in france and characterization of biochemical and clinical features.

Am J Ophthalmol 2015 Feb 5;159(2):302-14. Epub 2014 Nov 5.

Institut National de la Santé et de la Recherche Médicale, U1051, Institute for Neurosciences of Montpellier, Montpellier, France; University of Montpellier 1, Montpellier, France; University of Montpellier 2, Montpellier, France; CHRU, Genetics of Sensory Diseases, Montpellier, France.

Purpose: To assess the prevalence of PRPH2 in autosomal dominant retinitis pigmentosa (adRP), to report 6 novel mutations, to characterize the biochemical features of a recurrent novel mutation, and to study the clinical features of adRP patients.

Design: Retrospective clinical and molecular genetic study.

Methods: Clinical investigations included visual field testing, fundus examination, high-resolution spectral-domain optical coherence tomography (OCT), fundus autofluorescence imaging, and electroretinogram (ERG) recording. PRPH2 was screened by Sanger sequencing in a cohort of 310 French families with adRP. Peripherin-2 protein was produced in yeast and analyzed by Western blot.

Results: We identified 15 mutations, including 6 novel and 9 previously reported changes in 32 families, accounting for a prevalence of 10.3% in this adRP population. We showed that a new recurrent p.Leu254Gln mutation leads to protein aggregation, suggesting abnormal folding. The clinical severity of the disease in examined patients was moderate with 78% of the eyes having 1-0.5 of visual acuity and 52% of the eyes retaining more than 50% of the visual field. Some patients characteristically showed vitelliform deposits or macular involvement. In some families, pericentral RP or macular dystrophy were found in family members while widespread RP was present in other members of the same families.

Conclusions: The mutations in PRPH2 account for 10.3% of adRP in the French population, which is higher than previously reported (0%-8%) This makes PRPH2 the second most frequent adRP gene after RHO in our series. PRPH2 mutations cause highly variable phenotypes and moderate forms of adRP, including mild cases, which could be underdiagnosed.
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http://dx.doi.org/10.1016/j.ajo.2014.10.033DOI Listing
February 2015

Frequency and clinical pattern of vitelliform macular dystrophy caused by mutations of interphotoreceptor matrix IMPG1 and IMPG2 genes.

Ophthalmology 2014 Dec 29;121(12):2406-14. Epub 2014 Jul 29.

Centre de Référence Maladies Sensorielles Génétiques, Hôpital Gui de Chauliac, Montpellier, France; Montpellier University, Montpellier, France; Institute for Neurosciences, INSERM, Montpellier, France.

Purpose: To assess the frequency of and to characterize the clinical spectrum and optical coherence tomography findings of vitelliform macular dystrophy linked to IMPG1 and IMPG2, 2 new causal genes expressed in the interphotoreceptor matrix.

Design: Retrospective epidemiologic, clinical, electrophysiologic, and molecular genetic study.

Participants: The database of a national referral center specialized in genetic sensory diseases was screened for patients with a macular vitelliform dystrophy without identified mutation or small deletion or large rearrangement in BEST1 and PRPH2 genes. Forty-nine families were included.

Methods: Clinical, imaging, and electro-oculogram findings were reviewed. Mutation screening of IMPG1 and IMPG2 genes were performed systematically.

Main Outcome Measures: Frequency, inheritance, and clinical pattern of vitelliform dystrophy associated with IMPG1 and IMPG2 mutations were characterized.

Results: IMPG1 was the causal gene in 3 families (IMPG1 1-3, 11 patients) and IMPG2 in a fourth family (2 patients). With an autosomal dominant transmission, families 1 and 2 had the c.713T→G (p.Leu238Arg) mutation in IMPG1 and family 4 had the c.3230G→T (p.Cys1077Phe) mutation in IMPG2. Patients with IMPG1 or IMPG2 mutations had a late onset and moderate visual impairment (mean visual acuity, 20/40; mean age of onset, 42 years), even in the sporadic case of family 3 with a presumed recessive transmission (age at onset, 38 years; mean visual acuity, 20/50). Drusen-like lesions adjacent to the vitelliform deposits were observed in 9 of 13 patients. The vitelliform material was above the retinal pigment epithelium (RPE) at any stage of the macular dystrophy, and this epithelium was well preserved and maintained its classical reflectivity on spectral-domain optical coherence tomography (SD-OCT). Electro-oculogram results were normal or borderline in 9 cases.

Conclusions: IMPG1 and IMPG2 are new causal genes in 8% of families negative for BEST1 and PRPH2 mutations. These genes should be screened in adult-onset vitelliform dystrophy with (1) moderate visual impairment, (2) drusen-like lesions, (3) normal reflectivity of the RPE line on SD-OCT, and (4) vitelliform deposits located between ellipsoid and interdigitation lines on SD-OCT. These clinical characteristics are not observed in the classical forms of BEST1 or PRPH2 vitelliform dystrophies.
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http://dx.doi.org/10.1016/j.ophtha.2014.06.028DOI Listing
December 2014

Five year follow-up of two sisters with type II sialidosis: systemic and ophthalmic findings including OCT analysis.

J Pediatr Ophthalmol Strabismus 2013 Jul 2;50 Online:e33-6. Epub 2013 Jul 2.

Service d’Exploration Fonctionnelle de la Vision et Neuro Ophtalmologie, Hopital Roger Salengro, Lille, France.

The authors report a 5-year follow-up examination of two sisters diagnosed as having a juvenile form of type II sialidosis. Diagnosis occurred during a routine ophthalmic examination when the girls were 5 and 3 years old after bilateral macular cherry-red spots were revealed. Main clinical findings were hypotonia, hepatosplenomegaly, hearing loss, dysostosis, and respiratory distress. Ophthalmic symptoms were low visual acuity and nystagmus. Spectral-domain optical coherence tomography examination showed increased reflectivity of the retinal ganglion cells. Sialidosis may present as a mild form with slow progression. The cherry-red spots may be the first clue for proper diagnosis of storage disease. Spectral-domain optical coherence tomography examination unveiled the accumulation of sialic acid in the retinal ganglion cells and could potentially be used to monitor the progression of storage diseases.
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http://dx.doi.org/10.3928/01913913-20130625-02DOI Listing
July 2013

Whole-exome sequencing identifies mutations in GPR179 leading to autosomal-recessive complete congenital stationary night blindness.

Am J Hum Genet 2012 Feb;90(2):321-30

Institut National de la Santé et de la Recherche Médicale, Paris, France.

Congenital stationary night blindness (CSNB) is a heterogeneous retinal disorder characterized by visual impairment under low light conditions. This disorder is due to a signal transmission defect from rod photoreceptors to adjacent bipolar cells in the retina. Two forms can be distinguished clinically, complete CSNB (cCSNB) or incomplete CSNB; the two forms are distinguished on the basis of the affected signaling pathway. Mutations in NYX, GRM6, and TRPM1, expressed in the outer plexiform layer (OPL) lead to disruption of the ON-bipolar cell response and have been seen in patients with cCSNB. Whole-exome sequencing in cCSNB patients lacking mutations in the known genes led to the identification of a homozygous missense mutation (c.1807C>T [p.His603Tyr]) in one consanguineous autosomal-recessive cCSNB family and a homozygous frameshift mutation in GPR179 (c.278delC [p.Pro93Glnfs(∗)57]) in a simplex male cCSNB patient. Additional screening with Sanger sequencing of 40 patients identified three other cCSNB patients harboring additional allelic mutations in GPR179. Although, immunhistological studies revealed Gpr179 in the OPL in wild-type mouse retina, Gpr179 did not colocalize with specific ON-bipolar markers. Interestingly, Gpr179 was highly concentrated in horizontal cells and Müller cell endfeet. The involvement of these cells in cCSNB and the specific function of GPR179 remain to be elucidated.
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http://dx.doi.org/10.1016/j.ajhg.2011.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3276675PMC
February 2012

Spinocerebellar ataxia: a rational approach to aetiological diagnosis.

Cerebellum 2012 Mar;11(1):289-99

Department of Neurology, EA 2683, IMPRT, IFR114, Université Lille Nord de France, CHRU, Lille, France.

The objective of this study was to determine the main causal diagnosis for spinocerebellar ataxia (SCA) in a geographically defined population of ataxia patients and to suggest a rational basis for choosing appropriate clinical and paraclinical assessments. Given the many aetiologies responsible for SCA, the diagnosis requires the performance of a wide range of paraclinical analyses. At present, there is no consensus on the diagnostic value of these examinations. Furthermore, most of the currently available data gathered by reference centres suffer from selection bias. We performed a prospective study of consecutive cerebellar ataxia patients referred by their family doctors to a university hospital in northern France. Multiple system atrophy and obvious secondary causes (e.g. alcoholism) were excluded by our screening process. The patient's family members were also assessed. Of the 204 patients examined, 47% presented autosomal dominant ataxia and 33% presented sporadic ataxia. Autosomal recessive ataxia was rare (8%) and age at onset was significantly earlier for this condition than for other forms. An aetiological diagnosis was established in 44% of patients, a plausible hypothesis could be formed in 13% of cases, and no diagnosis was made in the remaining 44%. Established diagnoses included SCA1, SCA2, SCA3 and SCA6 mutations, Friedreich's ataxia, and one rare case of ataxia associated with anti-glutamic acid decarboxylase antibodies. Two families presented ataxia associated with autosomal, dominant, optic atrophy with an OPA1 mutation. Mitochondrial diseases were suspected in about 10% of patients. In SCA, reliable determination of the transmission mode always requires the assessment of family members. Mitochondrial disease may be an emerging cause of ataxia. Metabolite assays appeared to be of little value when systematically performed and so should be prescribed only by metabolic disorder specialists in selected cases of sporadic and recessive ataxia. Ophthalmological examination was the most helpful physiological assessment.
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http://dx.doi.org/10.1007/s12311-011-0310-1DOI Listing
March 2012

Thickening of peripapillar retinal fibers for the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay.

Cerebellum 2011 Dec;10(4):758-62

Service d'Exploration de la Vision et Neuro-Ophtalmologie, Hôpital Roger-Salengro, Lille, France.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is characterized by the presence of myelinated retinal fibers. This typical feature is very helpful for the diagnosis but is not always observed in patients outside Quebec. Apart from phenotype variations, misinterpretation of the funduscopy may explain discrepancies and misdiagnosis. We analyze the modification of retinal fibers layer using the funduscopy and the optical coherence tomography (OCT) in two French patients having spinocerebellar ataxia associated with a spastic paraparesia with genetically confirmed ARSACS. In both patients the funduscopy showed a swollen and striated aspect of peripapillar fibers along the retinal vessels and in the intermaculopapillar region. The OCT displayed an important thickening of the optical fibers layer mainly in upper and lower temporal area without attenuation of deep layers, as well as a filling in of the foveolar depression with thickening of the ganglion cell layer normally absent from the foveola. The aspect of funduscopy and OCT in our patients does not correspond to the classical description of myelin fibers encountered in 0.3% to 1% of the population. Thus, ARSACS might be underdiagnosed because of an erroneous interpretation of funduscopy. When considering the diagnosis of ARSACS, the neurologist should ask the ophthalmologist to search for thickening of peripapillar retinal fibers by both funduscopy and OCT rather than myelinated retinal fibers. This ophthalmological consideration has avoided misdiagnosis and led to the description of new mutations in our cases.
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http://dx.doi.org/10.1007/s12311-011-0286-xDOI Listing
December 2011

Fearful faces impact in peripheral vision: behavioral and neural evidence.

Neuropsychologia 2011 Jun 29;49(7):2013-21. Epub 2011 Mar 29.

Université de Lille Nord de France, F-59000, France.

Many studies provided evidence that the emotional content of visual stimulations modulates behavioral performance and neuronal activity. Surprisingly, these studies were carried out using stimulations presented in the center of the visual field while the majority of visual events firstly appear in the peripheral visual field. In this study, we assessed the impact of the emotional facial expression of fear when projected in near and far periphery. Sixteen participants were asked to categorize fearful and neutral faces projected at four peripheral visual locations (15° and 30° of eccentricity in right and left sides of the visual field) while reaction times and event-related potentials (ERPs) were recorded. ERPs were analyzed by means of spatio-temporal principal component and baseline-to-peak methods. Behavioral data confirmed the decrease of performance with eccentricity and showed that fearful faces induced shorter reaction times than neutral ones. Electrophysiological data revealed that the spatial position and the emotional content of faces modulated ERPs components. In particular, the amplitude of N170 was enhanced by fearful facial expression. These findings shed light on how visual eccentricity modulates the processing of emotional faces and suggest that, despite impoverished visual conditions, the preferential neural coding of fearful expression of faces still persists in far peripheral vision. The emotional content of faces could therefore contribute to their foveal or attentional capture, like in social interactions.
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http://dx.doi.org/10.1016/j.neuropsychologia.2011.03.031DOI Listing
June 2011

Phenotypic variability in a French family with a novel mutation in the BEST1 gene causing multifocal best vitelliform macular dystrophy.

Mol Vis 2011 Jan 29;17:309-22. Epub 2011 Jan 29.

Université Paris-Descartes, Faculté de Médecine Paris Descartes-site Necker, CERTO, Paris, France.

Aims: To describe genetic and clinical findings in a French family affected by best vitelliform macular dystrophy (BVMD).

Methods: We screened eight at-risk members of a family, including a BVMD-affected proband, by direct sequencing of 11 bestrophin-1 (BEST1) exons. Individuals underwent ophthalmic examination and autofluorescent fundus imaging, indocyanine green angiography, electro-oculogram (EOG), electroretinogram (ERG), multifocal ERG, optical coherence tomography (OCT), and where possible, spectral domain OCT.

Results: The sequence analysis of the BEST1 gene revealed one previously unknown mutation, c.15C>A (p.Y5X), in two family members and one recently described mutation, c.430A>G (p.S144G), in five family members. Fundus examination and electrophysiological responses provided no evidence of the disease in the patient carrying only the p.Y5X mutation. Three patients with the p.S144G mutation did not show any preclinical sign of BVMD except altered EOGs. Two individuals of the family exhibited a particularly severe phenotype of multifocal BVMD-one individual carrying the p.S144G mutation heterozygously and one individual harboring both BEST1 mutations (p.S144G inherited from his mother and p.Y5X from his father). Both of these family members had multifocal vitelliform autofluorescent lesions combined with abnormal EOG, and the spectral domain OCT displayed a serous retinal detachment. In addition, ERGs demonstrated widespread retinal degeneration and multifocal ERGs showed a reduction in the central retina function, which could be correlated with the decreased visual acuity and visual field scotomas.

Conclusions: A thorough clinical evaluation found no pathological phenotype in the patient carrying the isolated p.Y5X mutation. The patients carrying the p.S144G variation in the protein exhibited considerable intrafamilial phenotypic variability. Two young affected patients in this family exhibited an early onset, severe, multifocal BVMD with a diffuse distribution of autofluorescent deposits throughout the retina and rapid evolution toward the loss of central vision. The other genetically affected relatives had only abnormal EOGs and displayed no or extremely slow electrophysiological evolution.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3032275PMC
January 2011

Systematic screening of BEST1 and PRPH2 in juvenile and adult vitelliform macular dystrophies: a rationale for molecular analysis.

Ophthalmology 2011 Jun 26;118(6):1130-6. Epub 2011 Jan 26.

Centre de Référence Maladies Sensorielles Génétiques, Hôpital Gui de Chauliac, Montpellier, France.

Purpose: To evaluate a genetic approach of BEST1 and PRPH2 screening according to age of onset, family history, and Arden ratio in patients with juvenile vitelliform macular dystrophy (VMD2) or adult-onset vitelliform macular dystrophy (AVMD), which are characterized by autofluorescent deposits.

Design: Clinical, electrophysiologic, and molecular retrospective study.

Participants: The database of a clinic specialized in genetic sensory diseases was screened for patients with macular vitelliform dystrophy. Patients with an age of onset less than 40 years were included in the VMD2 group (25 unrelated patients), and patients with an age of onset more than 40 years were included in the AVMD group (19 unrelated patients).

Methods: Clinical, fundus photography, and electro-oculogram (EOG) findings were reviewed. Mutation screening of BEST1 and PRPH2 genes was systematically performed.

Main Outcome Measures: Relevance of age of onset, family history, and Arden ratio were reviewed.

Results: Patients with VMD2 carried a BEST1 mutation in 60% of the cases. Seven novel mutations in BEST1 (p.V9L, p.F80V, p.I73V, p.R130S, pF298C, pD302A, and p.179delN) were found. Patients with VMD2 with a positive family history or a reduced Arden ratio carried a BEST1 mutation in 70.5% of cases and in 83% if both criteria were fulfilled. Patients with AVMD carried a PRPH2 mutation in 10.5% of cases and did not carry a BEST1 mutation. The probability of finding a PRPH2 mutation increased in the case of a family history (2/5 patients). Electro-oculogram was normal in 3 of 15 patients with BEST1 mutations and reduced in the 3 patients with PRPH2 mutations.

Conclusions: Age of onset is a major criterion to distinguish VMD2 from AVMD. Electro-oculogram is not as relevant because decreased or normal Arden ratios have been associated with mutations in both genes and diseases. A positive family history increased the probability of finding a mutation. BEST1 screening should be recommended to patients with an age of onset less than 40 years, and PRPH2 screening should be recommended to patients with an age of onset more than 40 years. For an onset between 30 and 40 years, PRPH2 can be screened if no mutation has been detected in BEST1.

Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
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http://dx.doi.org/10.1016/j.ophtha.2010.10.010DOI Listing
June 2011